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The RNA revolution: How our understanding of life's blueprint is being rewritten

For decades, the central dogma of molecular biology—DNA makes RNA, RNA makes protein, protein makes phenotype—was the guiding framework for understanding inheritance and disease. This model explained classic Mendelian traits, such as how single DNA mutations in protein-coding regions could cause diseases like sickle cell anemia. Yet, this accounts for only about 2% of Mendelian inheritance and the resulting phenotypic changes.

The vast majority of mutations that influence phenotype—nearly all, in fact—are found not in protein-coding regions, but in regulatory regions and among the vast population of noncoding RNAs. These RNAs, many of which do not code for large proteins, play critical roles in controlling gene expression and, ultimately, phenotypes.

There are two reasons for this. First, the sheer number of RNAs is enormous. Second, even some RNAs long considered "noncoding" actually produce hundreds of thousands of small peptides, with estimates reaching up to 200,000. From a genetic perspective, this means there are more than ten times as many functional genes as we previously thought defined us.

I had an early inkling of this when I was directing the science at Human Genome Sciences. After we found the first 20,000 protein-coding genes, we kept finding more RNAs—over ten times as many—long, stable, polyadenylated, capped RNAs. At the time, we tentatively suggested these might be meaningful.

Now we know: many are functional RNAs, and when mutated, they can give rise to specific phenotypes. Some of these long noncoding RNAs even produce small peptides, and mutations in those can also cause phenotypic changes.

We can think of this in terms of LEGO. You can build a simple or a complex structure from the same set of LEGO pieces. The proteins are the blocks—sometimes in different colors, representing variants—but the instructions, the regulatory RNAs, are what make the difference. This is why a worm and a human can have about the same number of genes, yet humans are vastly more complex. The complexity comes from the instructions, not just the building blocks.

Noncoding RNAs—including microRNAs, long noncoding RNAs, and others—as well as the peptides they encode, are the instruction manuals. They determine when, where, and how much of each protein "brick" is built. They do so by controlling gene expression at multiple levels. These RNAs can silence genes, remodel chromatin, and guide chemical modifications on both DNA and RNA.

Through editing, methylation, and other modifications, RNAs can change their own function or that of their targets, all without altering the underlying DNA sequence. Mutations in these RNAs or their encoded peptides can lead to specific phenotypes and diseases, expanding the functional gene count by at least an order of magnitude.

Let's look at a couple of real-world examples. First, consider that any RNA can play a regulatory role, and a single stretch of DNA can produce both a protein-coding RNA and a regulatory RNA. When cells are hit by ultraviolet or UV light, for instance, they switch from making a typical protein-coding RNA to a shorter, noncoding version from the same gene. This new RNA helps the cell recover from DNA damage, acting almost like a counterbalance to the protein produced by that gene.

Another fascinating twist: some so-called "noncoding" RNAs actually contain tiny instructions for making short peptides—little protein fragments that can have big effects. These micropeptides can influence everything from how cells grow and survive to brain development, to cancer progression. Some even act as hormones. In other words, what we once thought of as "junk" or "silent" RNA is often anything but.

RNA's role as a carrier of heritable information is not limited to its intermediary function. In some viruses, RNA is the primary genetic material. Retroviruses and retrotransposons use RNA to generate DNA, thereby integrating new genetic elements into the genome—a process that has shaped approximately half of the human genome and continues to influence aging and cancer.

The expanded dogma now recognizes a multidirectional flow of genetic information. This model reflects not only the traditional flow from DNA to RNA, but also RNA's ability to direct modifications of DNA, regulate gene expression, and even serve as a template for DNA synthesis in certain viruses and cellular processes. RNA's influence extends beyond the cell: RNAs can be transferred between cells and even across species boundaries via extracellular vesicles, influencing immunity, development, and disease.

The new dogma recognizes that biological systems are inherently redundant and flexible. RNA molecules can mimic, moonlight, and interact promiscuously, allowing one genotype to yield many phenotypes and one phenotype to arise from diverse genotypes. This plasticity underlies evolution, adaptation, and disease resilience.

This is not just a technical update; it's a conceptual leap. RNA is at the heart of biological complexity. The practical impact is profound. RNA-based vaccines and therapies are already transforming medicine. RNA interference and CRISPR-based technologies are advancing the fields of crop science and synthetic biology. The challenge now is to design RNAs that are stable, specific, and safely delivered to target cells—tasks that require a deep understanding of RNA's structural and functional diversity.

As someone who has witnessed the evolution of molecular biology, I'm both humbled and exhilarated by this RNA revolution. It's a reminder that science is not static; our models are provisional, our dogmas subject to revision. The genome is not a fixed blueprint, but a dynamic and responsive system, with RNA at its center. By embracing the complexity and versatility of RNA, we're poised to unlock new therapies, gain a deeper understanding of disease, and appreciate the true richness of life's molecular machinery.

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